JPH03181498A - Peptide antiviral agent - Google Patents

Abstract

NEW MATERIAL: A peptide (salt) of formula I [A¹ and A² are each isoleucine, leucine, valine, phenylglycine, etc.; A³ is formula II (R⁴ is H or methyl; R⁵ is amine, alkoxy, etc.), etc.; A⁴ is aspartic acid, etc.; A⁵ is formula III (R⁹ and R¹⁰ are each H, a C_1-6 alkyl, etc.), etc.; Ra is formula IV (R¹ is H or an alkyl; R" is cycloalkyl, phenyl, etc.; R³ is H, phenyl, etc.) or phenyl; m is 0 or 1; n is 1 or 2].

USE: Therapeutic agents for viral infections in mammals.

PROCESS: For example, a pentapeptide bonded to a resin of formula V is reacted with a substituted and activated acylating agent of formula VI (X is a halogen or pentafluorophenoxy) in the presence of an organic base, and the peptide is released from the resin to give the peptide of formula 1.

COPYRIGHT: (C)1991,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION Herpes simplex virus (H3V) causes a wide range of diseases ranging from mild to severe, including mucosal lesions, keratitis, and encephalitis. It has been reported that both H3VI type and type 2 are widely prevalent in Europe and America, and the proportion of people exposed to H3V-1 is estimated to be over 90%. many I(SV
The recent rapid increase in genital infections has been driven by serological studies, with 15-35% of North American infections being H3V-
This indicates that the person has been exposed to 2.

Most of the effort to develop anti-herpes drugs has historically focused on H3
The focus has been on nucleotide analogue inhibitors of V DNA polymerase. All of the treatments currently in use are nucleoside analogs and acyclovirus (acyclovirus).
ovir) is the main example. Oral or intravenous acyclovir is the treatment of choice for most infections. Topical Acyclovir, Widarabine (vidara)
(bine) or idoxuridine (idoxuridine)
ne) are all used for herpes cornea, which is the leading cause of corneal blindness in this country. However, given the complex replication cycle and the many encoded proteins of viruses, there must be other possible targets for antiviral drugs. H3V ribonucleotide reductase (RR) is one such target, and the virus-specific enzyme is significantly different from its mammalian counterpart. H3V-RR catalyzes the reduction of four ribonucleotides to the corresponding deoxyribonucleotides required for DNA replication. Published analyzes of virus RR mutants indicate that the enzyme is not essential for herpes growth in culture (Goldstein and Wel.
ler), Virology, Vol. 166, p. 41 (198
8)) was announced to be essential in vivo.

Herpes RR inhibitors themselves have anti-herpes activity (Shipman et al., Antiviral Research, Vol. 6, p. 197 (1986)), and also enhance or synergize the action of acyclonucleoside antiviral agents. (
Spector, etc., Proc, of
the Nat, Acad, of Sci, Vol. 86, p. 1051 (1989)).

Dutia et al. Nature Volume 321, 43
9-441 (1986) and Cohen
) et al., Nature Vol. 321, pp. 441-443 (19
1986) and U.S. Pat. No. 4,795,740 both disclose the nonapeptide Thr Ala Gly Ala Val
It is disclosed that ValAsn Asp Leu inhibits the activity of this enzyme in vitro. Furthermore, Duchia et al., in the cited document cited above, described its 8-desalanine homolog, Ty
r Gly Ala Val Val Asn Asp
Leu has also been disclosed to inhibit the activity of this enzyme in vitro.

Gaudreau et al., J. Biol
, Chemistry Vol. 262, p. 12413 (1987) discloses structure-activity studies of the above-mentioned nonapeptide analogs. Garsky and Stein
No. 4,837,304 discloses a series of oligopeptides shown to inhibit the activity of the RR enzyme in vitro.

The object of the present invention is to treat viruses, especially viruses of the herpes family,
In particular, it is an object to provide novel substituted peptides that inhibit the activity of the herpes simplex virus nucleotide reductase enzyme. Another object is to provide inhibitor peptides that have no or weak activity against the mammalian enzyme nucleonucleotide reductase.

A series of substituted peptides were found to inhibit the activity of the herpes simplex virus nucleotide reductase enzyme in vitro.

The present invention provides formula I ■ and A2 independently isoleucine, Leucine, norleucine, Balin, cyclohexylgly Shin, f) Phenylglycine, g) N-methylisoleucine, h) N-methylvaline, i) Phenylalanine, j) N-methylleucine or any of their enantiomers.

A3 is 4 -N-CH-CO- C) 12c(0)R5 (R' is hydrogen or methyl.

RS is -OR' or -NR'R7 (R6 and R7 are independently j) hydrogen, k) C3-C, cycloalkyl, 1) C6-C, cycloalkenyl, 111) phenyl, n) NH2, C+ ~ Ca 7 Lucil, SR
” phenyl substituted with C0zll or OR',
(R8 is H or C, -C, alkyl.) 0) Polycyclic aromatic, p) CIA-C, alkyl, q) C, -C, mono-substituted with k) to n) above is alkyl, or R6 and R7 combine to form a diradical, or -NR'R' is morpholino).

A4 is aspartic acid, N-methylaspartic acid or any of their enantiomers.

A5 is the formula % expression % (0) is defined above.

and R1 (+ is independently hydrogen, C7-C6 alkyl, monofluoroalkyl, C3-C6 alkenyl, C4-C, cycloalkyl, or R9 and R1
0 is bonded to form a C3-C diradical).

3 le (R' is H or C1-C6 alkyl.

R2 is w) C, ~C7 cycloalkyl, x) Cs ~
C, cycloalkenyl, y) phenyl, z) NH2, C+~Ca alkyl, -SR'-co
phenyl substituted 1 to 3 times with zu, halogen or -OR' (R11 is H or C1-C4 alkyl) aa) polycyclic aromatic ring, substitution of w) to aa) on bb) group, -CO2H or -N
01-C4 alkyl substituted with one of HR” (R”
is H or -COzC1hC6Hs. ) or R2 is H or C1 to C are also alkyl when m is 1.

R3 is cc) hydrogen, dd) phenyl, ee) -NHz, fer, C1-C4 alkyl,
Halogen, SR' C0zll or -OR" 1
~trisubstituted phenyl (Ra H, c, -c, alkyl or phenyl), ff) polycyclic aromatic radical, gg) heteroaromatic ring system, hh) dd) ~ gg) or C3-C4 alkyl substituted 1 or 2 times independently with -cozH, ti) NHR"(R" is above (7)hh) or hydrogen,
01-C6 alkyl, -CH2COJ or -C(0)
CHRI3Nflz and R''' is C1-C4 alkyl monosubstituted with H or -SR' or -CO□H).

m is 0 or l.

n is 1 when m is 0, and 2 when m is 1. ] A novel substituted peptide compound represented by the following is provided.

However, AI and A2 are both valine, R' is hydrogen, R5 is -NR'R7, Rh is hydrogen, and R
When 7 is hydrogen or benzyl, A4 is aspartic acid, A5 is leucine, and m is O, R2
is C, -C mono-substituted with one of the substituents -) to aa)
, not alkyl.

The present invention also provides pharmaceutically usable salts of the above compounds.

"Alkyl, alkenyl and alkynyl'" is intended to include straight and branched chain structures.

"Alkyl" is intended to include methyl, ethyl, propyl, isopropyl, butyl, 5ec- and tert-butyl, pentyl, hexyl, and the like.

"Alkenylp" includes vinyl, allyl, isopropenyl, pentenyl, hexenyl, etc.

"Alkynyl" includes ethynyl, propynyl, butynyl, etc.

° "Cycloalkyl" shall include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

``Cycloalkylpa includes cyclopentenyl, cyclohexenyl, cyclohebutenyl, etc.

The term "heteroaromatic ring system" includes pyridine, thiophene, furan, and the like.

The term "heteroaromatic polycyclic ring system" includes quinoline, isoquinoline, indole, benzofuran, benzothiophene, and the like.

The term "aromatic polycyclic ring system" includes naphthalene, phenanthrene, and the like.

"Halogen" shall include fluorine, chlorine, bromine or iodine ions.

Some of the compounds described herein contain one or more asymmetric centers and are therefore capable of giving rise to diastereomers and optical isomers. The present invention is meant to cover such diastereomers as well as racemic and resolved optically active forms.

Some of the compounds described herein contain olefinic double bonds and are meant to include both E and Z geometric isomers, unless otherwise specified.

Preferably A3 is of the formula % (0) (R' is hydrogen, R3 is -NR6R'l' and R7 are independently hydrogen, methyl, ethyl, benzyl or R& and R7 are combined) C1 to C, forming a diradical, or -NR'R' is morpholino).

Preferably A5 is an amino acid residue having the formula %(0) where R' and R9 are hydrogen and RIG is t-butyl or isopropyl.

Preferably R1 is hydrogen.

Preferably R2 is phenyl, benzyl or -NH.

C+~C4 alkyl, -5R" -CO2ll or -
phenyl or benzyl substituted with OR', R1
1 is H or C0-C4 alkyl.

One aspect of the invention includes a pharmaceutical composition comprising an antiherpesviral effective amount of a compound of formula I or a therapeutically usable salt thereof and a carrier that can be used pharmaceutically or veterinary therapeutically.

Another aspect of the present invention is a method for treating a herpesvirus infection in a mammal by administering to the mammal an anti-herpesvirus effective amount of a peptide of formula (1) or a pharmaceutically usable salt thereof as hereinafter defined. including.

Another aspect of the invention provides a method of treating a viral infection in a mammal, comprising administering to the mammal an antiviral effective amount of a peptide of Formula I and another antiviral acyclonucleoside or related compound. include.

A method for producing the peptide of formula (II) is described below.

It has now been found that a series of substituted pentapeptides inhibit the activity of the herpes simplex virus ribonucleotide reductase enzyme in vitro. This enzyme is required for the in vivo replication of herpes simplex virus. The inhibitory activity has been shown to be virus specific in vitro and has no effect on mammalian reductase enzymes.

The peptides of the invention and their acids and salts can be prepared according to known synthetic methods, i.e. by stepwise condensation of amino acids or initially by Merrifield.
) J, Am, Chem, Soc, Volume 85, 2
149-2154 (1963) or by using an automatic peptide synthesizer. The N-substituent can then be attached to the pentapeptide unit according to known synthetic methods, namely by reaction with the corresponding activating acylating agent in the presence of an organic nitrogen base. Examples of activated acylating agents can be acid chlorides, acid anhydrides, pentafluorophenyl esters, and carbamyl chlorides.

Condensation between two amino acids can be carried out using conventional condensation methods such as the azide method, mixed acid anhydride method, DCC (dicyclohexylcarbodiimide) method, N-hydroxysuccinimide method, cyano method, Woodward reagent method, and carbonyldiimidazole method. Alternatively, it can be carried out according to an oxidation-reduction method. These condensation reactions can be carried out in a liquid phase or a solid phase. When elongating a peptide chain using a solid phase method, the peptide is attached to an insoluble carrier at the C-terminal amino acid. Examples of insoluble carriers that react with the carboxyl group of the C-terminal amino acid and are easily cleaved later include halomethyl resins, such as chloromethyl resins, bromomethyl resins, benzhydrylamine resins, and t-alkoxycarbonyl hydrazide resins. can be used.

As usual in peptide synthesis, α
It is necessary to protect/deprotect the - and λ- side chain amino groups and the carboxy groups of the agonoic acids. Examples of protective groups that can be used for amino groups include benzyloxycarbonyl (hereinafter abbreviated as Z), O-chlorobenzyloxycarbonyl (Z(2-C1)), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(-0Me)), t-butoxycarbonyl (BOC), t-amyloxycarbonyl (Aoc), isobornyloxycarbonyl (B p
oc), 9-fluorenylmethoxycarbonyl (F
moc), methylsulfonylethoxycarbonyl (M
sc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenyl sulfenyl (NFS), diphenylphosphinothioyl (Ppt), dimethylphosphinothioyl (MPT), and the like.

Examples of protective groups for carboxyl groups include benzyl ester (OBZI), 4-nitrobenzyl ester (OBzl(NOx)), and t-butyl ester (OBZI).
ut), 4-pyridylmethyl ester (OPic), and the like. It is desirable that certain amino acids such as arginine, cysteine, and serine, which have functional groups other than amino and carboxyl groups, be protected with appropriate protecting groups depending on the case. For example, the guanidino group of arginine is nitro, p-toluenesulfonyl, benzyloxycarbonyl, adamantyloxycarbonyl,
p-methoxybenzenesulfonyl, 4-methoxy-2,
3゜6-drimethylbenzenesulfonyl (Mtr),
4methoxy-2,6-dimethylbenzenesulfonyl (M
ds), 1. 3. It can be protected with 5-trimethylphenylsulfonyl (Mts) or the like. The thiol group of cysteine can be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetylamitumethyl, ethylcarbamoyl, 4-methylbenzyl, 2,4.6-drimethylbenzyl (Tmb), etc. The hydroxy group of can be protected with benzyl, t-butyl, acetyl, tetrahydropyranyl, etc.

For example, Schroder, et.
6 years, or Macaw” < - (McOmie) (m)
``Protective Group in Organic Chemistry,'' Plenum Press, 1973, or the peptides described by Barany et al., ``The Peptides: Analysis, Synthesis, Biology,'' Volume 2, Chapter 1, Academic Press, 1980. cites a certain common law disclosure.

The pharmaceutical compositions of the present invention include a compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and may further include a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. "Pharmaceutically acceptable salts" means salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases.

Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganic, potassium, sodium, zinc salts. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically usable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amino and basic ion exchange resins such as arginine, Betaine, caffeine, choline, N,N'-dibenzylethylenediamino, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenecyamino, N-ethylmorpholine, N-ethylpiperidine, glucamine, gelcosa Contains ξ, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, boryan resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, trimetadan and the like.

When the compound of the invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid,
Hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid,
Malic acid, mandelic acid, methanesulfonic acid, mucilage acid, nitric acid, bamoic acid, pantothenic acid, phosphoric acid, succinic acid,
Contains sulfuric acid, tartaric acid, p-+-luenesulfonic acid, etc. Especially citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid,
Sulfuric acid and tartaric acid are preferred.

In an aspect of the invention there is provided a pharmaceutical composition or process for preparing a compound of formula I as defined above or a therapeutically usable salt thereof and a pharmaceutically acceptable carrier thereof.

In particular embodiments, the pharmaceutical compositions include a compound of the invention in effective unit dosage form.

As used herein, "effective unit dosage" or "effective unit dosage" is intended to mean a predetermined antiviral amount that is sufficiently effective against viral organisms in vivo. There is. A pharmaceutically acceptable carrier is a substance useful for the purpose of administering a drug, which can be a solid, liquid or gaseous substance, and which is inert, pharmaceutically acceptable and compatible with the active ingredient. It is something.

These pharmaceutical compositions may be administered parenterally, orally, or
It can be used as a herbal medicine or pessary, or topically as an ointment, cream, aerosol, powder, or administered as eye drops or nasal drops, and the formulation can be used to treat either internal or external viral infections. Depends on how you use it.

Against internal infections these compositions are effective against 1 kg of mammalian body weight.
It is administered orally or parenterally at a dosage level of about 0.1 to 250 μ per unit dose, preferably 1.0 to 50 μ per unit dose; Used in unit dosage form to be administered several times a day.

Finely divided powders or granules for oral administration may contain diluents, dispersants and/or surfactants, and in water or syrup for draft; dry or non-containing for capsules or sachets. Aqueous solution or suspension (!Q
tablets which may contain binders and lubricants; or suspensions in water or syrups. Flavoring agents, preservatives, suspending agents, thickening agents or emulsifying agents may be included if desired or necessary. Tablets and granules are suitable and can be coated.

For parenteral administration or administration such as eye drops in the case of ocular infections, these compounds are present in aqueous solutions at about 0.1-10%;
Preferably it may be present at a concentration of 0.1-7%, optimally 0.2% w/v. This solution can contain antioxidants, buffers, and the like.

Also, for infections of the eye or other external tissues such as the mouth and skin, these compositions are preferably applied as a topical ointment or cream to the infected area of the patient's body. The compound may be present in an ointment, e.g. with a water-soluble ointment base, or in a cream, e.g. with an oil in a water cream base, in an amount of about 0.1 to 10
%, preferably 0.1-7%, optimally 1% H/v.

The following examples specifically illustrate the present invention, but are not intended to limit the invention. All temperatures are given in °C.

Example I L-tyrosyl-L-valyl-L-valyl-L-asparagyl-shi-aspartyl-L-(γ-methyl)leucine Commercially available PepSyn K A resin and N-9-fluorenylmethoxycarbonyl-penta The title compound was synthesized using a Millian 905 platform peptide synthesizer using the corresponding peptide units commercially available as fluorophenyl esters.

Polypeptide resin product from synthesizer:
Treated with 4:1 trifluoroacetic acid:1,2-ethanedithiol:thioanisole followed by 80% aqueous acetic acid. The crude product in solution was then purified by reverse phase HPLC to yield the title compound.

p, m, r, (IhO) δ: 0.87-0.9
8 (4d, 12H), 0.90 (s.

9H), 1.65-1.78(dq, 28), 1
．． 93-2.08 (m, 2H), 2.70-2.90
(dq, 4H) , 3.11 (d, 211) , 4
．． 03.4.14(t, 2+1), 4.28(t,
IH), 4.32 (dd, IH), 6.85°7
．． 81 ppm (q, 411); M, S, (FA
B): Dan/e 736 (M+H)'' The following compound was prepared in a similar manner.

L-tyrosyl-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-(2-allylglycine)
, L-tyrosyl-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-isoleucine, L-phenylalanyl-L-valyl-L-valyl-L-
(0-methyl)aspartyl-L-aspartyl-
Leucine, L-tyrosyl-L-valyl-L-valyl-L-asparagyl-L-aspartyl-D, L-(α-methyl)leucine, L-tyrosyl-L-valyl-shi-valyl-L-asparagyl -L-aspartyl-aminocyclopropanecarboxylic acid, L-tyrosyl-L-leucyl=L-valyl-L-asparagyl-L-aspartyl-L-leucine, glycyl-
L-tyrosyl-L-valyl-L-valyl-L-(0-methylaspartyl)-L-aspartyl-L-leucine and L-tyrosyl-L-(N-methylvalyl)-L-valyl to L-asparagyl L-aspartyl to L-leucine.

Example 2 L-aspartyl-L-valyl-L-valyl-L-(N
' , N'-dimethylasparagyl)-L-aspartyl-L-leucine Step A: N-carbobenzyloxyaspartic acid α ~
Benzyl-T-P-nitrophenyl diester A solution of 1.798 g of N-carbobenzyloxyaspartic acid α-benzyl ester and 835 mg of p-nitrophenol in 10 g of ethanol was cooled to O'C and diluted with EtOAc.
c) Treated with a solution of 1.03 g of dicyclodicyclohexylcarbodiimide C) in 3 rtdl. Add this mixture to 0
Stirred at °C for 45 minutes then at room temperature (RT) for 2 hours.

The mixture was filtered and the solids were washed with EtOAc.

The combined filtrates were concentrated under vacuum and the residue was recrystallized from hot EtOH with 1% acetic acid to give the title compound.

Two aids: N-carbobenzyloxy-N',N'-dimethylasparagine benzyl ester 11nomethanol 2 and dimethylamine hydrochloride 613 in EtOAc I0- and diisopropylethylamine 1,3
To 6 ml of the solution was added a solution of the diester obtained in step A (3 g) in EtOAc at O'C. Add this mixture to O
'C for 30 min, then at RT overnight. The solution was then concentrated under vacuum and the residue was dissolved on silica gel (
2:1 Hexa7: Et, OAc, next.

Flash chromatography with 2:1 EtOAc:hexane) gave the title compound.

Step C: N',N'-dimethylasparagine acetic acid 50m
1 and t+, o25d middle step B ester 2.1g and 10
The mixture of % Pd/CI 00■ was shaken under hydrogen atmosphere for 2 hours. The mixture was then filtered through Celite and concentrated under vacuum. The residue was dissolved in methanol and filtered through decolorizing carbon.

The filtrate was concentrated under vacuum to give the title compound.

Process DEN-(fluorenylmethoxycarbonyl)-N
'N'-dimethylasparagine methylene chloride 10
A solution of asparagine (441 .mu.) from Step C and 595 .mu. of trimethylchlorosilane was refluxed for 1 hour in rnl. The mixture was then cooled to 0°C and treated with 1.44 wft of diisopropylethylamine. After this mixture became a homogeneous solution, 711 μg of 9-fluorenylmethyl chloroformate was added, and the solution was heated at O'C for 20 minutes.
It was then stirred for 1 hour at RT. The solution was then concentrated in vacuo and the residue was dissolved in a mixture of 40 d of ethyl ether and 50 d of 5% aqueous bicarbonate. The layers were separated and the aqueous phase was washed twice with ethyl ether. The combined organic phases were back-extracted with water and the combined aqueous phases were acidified to p)12. The aqueous mixture was then extracted with ethyl ether (3 x 60 mj! each) and the combined organic phases were dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give the title compound, which was used directly in the next reaction.

Step E: N-(fluorenylmethoxycarbonyl)-N
', N'-Dimethylasparagine pentafluorophenyl ester The substituted asparagine (545 µ) was treated with 263 µ of pentafluorophenol, and the mixture was dissolved in ethyl acetate lO-. The solution was cooled to o'c and a solution of 295 μm of DCC in 5-ethyl acetate was added. The mixture was stirred for 45 minutes at 0° C. and then for 75 minutes at RT. The mixture was filtered through a pad of Celite and concentrated under vacuum. Flash chromatography of the residue on silica gel (1:1 ethyl acetate:hexanes) gave the title compound.

Engineering 1-p-: L-aspartyl-shi-valyl-L-valyl L-(N'N'-dimethylasparagyl)-L
-Aspartyl-L-Leucine The title compound was prepared using the peptide platform machine procedure of Example 1, except that the commercially available unsubstituted asparagine was replaced with the ester of Step E.

p, m, r, (CD:1cO2D)δ: 0.85-
1.05 (m, 18H), 1.75 (m, 3H)
, 2.10 (m, 2H) , 2.88-3.20 (
m, 611), 2.92 (s, 311), 3.0
5 (s, 3H), 4.45 (m, 2H), 4.6
8(n+, 2H), 5. O2ppm+(m, 2H
) ;M,S, (FAB) :m/e 702 (
M+H)”.

The following compounds were prepared in a similar manner to Example 2 except substituting the corresponding amine in Step B.

L-tyrosyl-L-valyl-L-valyl-L-(N'-
ethyl-N'-methylasparagyl) L-aspartyl-L-leucine, L-tyrosyl-L-valyl-L-valyl-L-(N'
, N'-dimethylasparagyl)-L-aspartyl-
L-leucine, L-tyrosyl-L-valyl-L-valyl-L-(N'
, N'-(oxydiethylene)asparagyl)-L-
Aspartyl-L-leucine, L-aspartyl-L-
Valyl-L-valyl-L-(N'N'-tetramethyleneasparagyl)-L-aspartyl-L-leucine,L-tyrosyl-L-valyl-L-valyl-L-(N'
, N'-tetramethyleneasparagyl)-L-aspartyl-L-leucine, L-tyrosyl-L-valyl-L-valyl-L(N',
N'-dimethylasparagyl)-L-aspartyl-L
-(r-methyl)leucine, L-methionyl-L-tyrosyl-s-valyl-Lvalyl-L-(N', N' -
dimethylasparagyl)-L-aspartyl-L-(γ
-methyl)leucine and L-tyrosyl-L-valyl-L-valyl-L-(N'-
methylasparagyl)-L-aspartyl-L-leucine.

Example 3 D-N-(2-benzyl-2-(4-methoxybenzyl)acetyl)-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine and L-N-(2 -benzyl-2-(4-methoxybenzyl)acetyl)-L-valyl-L-valyl-L-asparagyl-L-asunokurati JLe L-leucine Step A: 2-benzyl-2-(4-methoxy benzyl)
A solution of 1.78 m of 2.5 M n-butyllithium in hexane and 0673 m of soisopropylamine in acetic acid THFHF was stirred at O''C for 1 h. A solution of 288 m of 3-(4-methoxyphenyl)propanoic acid in THF was added and the mixture was stirred for 1 hour at RT. Hexamethylphosphoramide (0,317 ml) was added and the mixture was further stirred at RT.
The mixture was stirred at T for 10 minutes. The solution was then cooled to O'C and 0.190% of benzyl bromide was quickly added. The solution was stirred at RT for 1 h and cooled to O'C. 1N Hcf.
The solution was brought to pH 2 by adding fi aqueous solution. This mixture was then extracted four times with chloroform. The combined organic extracts were washed twice with water and then with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Flash chromatography of the residue on silica gel (50:1 methylene chloride:methanol) gave the title compound.

Kodandan: D, L-2-benzyl-2-(4-methoxybenzyl)acetic acid pentafluorophenyl ester Example 2, Example 2 except that asparagine in Step E was replaced with Example 3 and the acid in Step A , Step E to obtain the title compound.

Step C: D, L-N-(2-benzyl-2-(4-methoxybenzyl)acetyl)-L valyl-L-valyl-L-asparagyl-L-(0-t
-butyl)aspartyl-L-leucyl-Merrifield resin anhydrous dioxane 1.5 in L-valyl-L-valyl-L
-Asparagyl-L-(0-t-butyl)aspartyl-L-leucyl-Merrifield resin (Biosearch 9
A mixture of 433 μg (manufactured using a 500 automatic peptide synthesis machine) was stirred for 30 minutes. Anhydrous dioxane 1.5 d Middle step B
A solution of the ester (305 ml) and 0.122 d of diisopropylethylamine was added and the mixture was stirred for 6 days at RT in a sealed vial with a mechanical stirring shaft. At the end of this period, the mixture was filtered and the collected solids were washed three times with ethyl ether 4Id and three times with methylene chloride.
Washed twice. The solid was then dried under vacuum to yield the title compound.

Step D: D-N-(2-benzyl-2-(4-methoxybenzyl)-acetyl)-L=valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine and L-N-( Resin-bound peptide obtained in Step C 440■, Anisole 0
．． A mixture of 7 d and 6 m of hydrofluoric acid (HF) was stirred at RT for 1 hour. Remaining HF was removed under a stream of N2,
The residue was stirred in ethyl ether and filtered. The solids were then extracted with 30% aqueous acetic acid and the combined extracts were diluted with water to approximately 10% acetic acid concentration. This solution was freeze-dried to obtain 47 ml of fluff-like solid material. HPLC this solid.
Purification provided two isomers of the title compound.

Isomer A: p, n+, r, (CIhCOzD) δ: 0,44(
d, 3H), 0.65 (d, 3B) 0.85-1
．． 05 (m, 12H), 1.35 (m, IH)
, 1.60-1.82 (m, 4H), 2.68-3
．． 08 (m, 9H), 3.79 (s, 3H), 4.
22 (m, LH), 4.30 (m, 18), 4
．． 65 (m, IH), 4.96 (t, 28), 6
．． 79 (d, 2++), 7.06 (d, 2n),
7.15 (n+, IH), 7.75 ppm (m,
4H): M, S, (FAB): m/e 81
1 (M+H)” isomer B: p, m, r, (DzO)δ: 0.45 (d, 3H
), 0.63(d, 3H), 0.90-1.05(
m, 1211), 1.60-2.10 (m, 58
), 2.73-3.06 (n+, 9H), 3.73
(s, 3H), 4.19 (d, IH), 4.24
(d, 1ll) , 4.63 (R1, LH)
, 4.95 (t, 2H) , 6.80 (d,
2H), 7.17 ppm (a+, 7H)
;M, S, (FAB) :m/e 811
(M+H)”Example 4 L-(N-(2,2-dibenzylacetyl)valyl]-
L-valyl-L-aspargyl-L-aspartyl-L
-Leucine Using the method of Example 3, Steps B and C, except replacing the acid to the step with dibenzyl acetic acid, the title compound was obtained.

p, m, r, (DzO)δ: 0.37 (d, 38
), 0.60 (d, 3B), 0.86 (n+, 1
28), 1.59 (n+, 38), 2.0 (m,
LH), 2.533.0 (m, 811), 3.06
(m, 1B), 3.71 (d, IH), 3.88
(d, IH) , 4.18 (m, 01) , 4.6
Bm, IH), 4.72 (m, LH), 7.44
(m, 1011), 7.80 (d, IH), 7.9
2 ppm (d, IH); Gate, S, (FAB): m/e 781 (M+
H)”.

The following compounds were synthesized using this method, except that dibenzyl acetic acid was replaced with the corresponding acid.

L-(N-(3,3-diphenylpropanoyl)valyl)-L-valyl-L-asparagyl-shi-aspartyl-L-leucine, L-(N-(2-benzylacetyl)valyl]-L-valyl L-asparagyl-L-aspartyl-L-leucine, L-(N-(2,2-diphenylacetyl)valyl)-
L-valyl-L-asparagyl-L-aspartyl-L
-Leucine.

Shipwrecked Shiko L-(N-(2,2-dibenzylacetyl)baryl)-
L-valyl-L-(N',N'-dimethylasparagyl)-L-aspartyl-L-Cr-methyl Leucine The Merrifield resin-bound peptide of Example 4 was converted into L-valyl-L-valyl-L-(N ',N'-dimethylasparagyl-di-aspartyl-L-leucylPepSyn
The title compound was obtained using the method of Example 4 except that K A resin was substituted.

p, m, r, (CIhCOzD)δ: 0.85-1
．． 05 (m, 21H), 1.63 (m, IH)
, 1.85 (wide s, 2H), 2.05 (m,
211), 2.70-3.10 (m, 1511)
, 4.20 (m, 2H) , 4.62 (dd
.

IH), 4.98 (m, 2H), 7.18
ppm (m, Loll); M, S, (F
AB) :mle 823 (M+H)"Daitoyoban 1 N-(p-hydroxyhydrocinnamyl)-Lvalyl-
L-baryl-L-asparagyl-L-aspartyl-cy-leucine! MA: t-butyl p-t-butoxyhydrocinnamate 1 p-hydroxyhydrocinnamate in 100 d dioxane
0 g of the solution was cooled to OoC and treated with concentrated sulfuric acid 10-. Isobutylene (50ffiR) was then added to the reaction solution and the mixture was shaken at RT for 3 hours.

The remaining isobutylene was removed and the solution was poured into a saturated solution of sodium bicarbonate. The aqueous mixture was extracted four times with EtOAc and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. Dissolve the crude oil in ether and dilute this solution with IN NaOH
Washed 6 times with aqueous solution. The organic solution was then dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (9:l hexanes:EtOAc) to give the title compound.

Step B: -t-butoxyhydrosilicon methanol 1
In step 6d, the solution of 968 ml of ester obtained in step A was mixed with 20 l of water.
It was treated with a solution of 600 ml of potassium hydroxide in n1. The mixture was refluxed overnight, then cooled to RT and filtered.

The filtrate was concentrated under vacuum. The residue was dissolved in water and the solution was cooled to 0″C. 2N HHCf aqueous solution was added to pf
(5) and the resulting white solid was collected and washed four times with water. The solid was dried under vacuum overnight with p,o to give the title compound.

U≦-: pt-butoxyhydrocinnamic acid pentafluorophenyl ester The title compound was obtained using the method of Example 2, Step E, except that the asparagine in Example 2 was replaced with the acid in Step B.

Koritan: N-(p-hydroxyhydrocinnamyl)
Example except that the final single peptide unit loaded into the L-valyl-L-valyl-asparagyl-L-aspartyl-leucine peptide synthesizer was replaced with pt-butoxyhydrocinnamate pentafluorophenyl ester. The title compound was obtained using method 1.

p, m, r, (CIhCOzD)δ: 0.84-0
．． 95 (m, 121+), 1.68 (m, 28)
, 2.56 (m, 2H) , 2.75-3.00 (
m, 4) 1), 4.30 (m, 28), 4.54
(m, 18), 4.91 (m+ 2H), 6.73
-7.00 (q, 4H), 7.78.7.80.7.
99.8.14.8.22 ppm (d, 5H); M, S, (FAB): mle 707 (M+H
)"Example 7 N-[2,2-bis(4-hydroxybenzyl)acetyl]-L-valyl-L-valyl-L-asparagyl-L
~Aspartyl-L-leucine Step A: 4-(t-butyldimethylsiloxy)benzoic acid THF 200d and dimethylformamide (DMF) 30
8.3 g of 4-hydroxybenzoic acid, t-butyldimethylsilyl chloride 15. A solution of Og and 25 g of imidazole was stirred at RT overnight. The solution was then concentrated under vacuum and the residue was dissolved in pH 7 buffer and water. This aqueous solution was extracted twice with EtOAc and then 3N hydrochloric acid (H(/
The mixture was made acidic with an aqueous solution. This aqueous solution was then diluted with EtOAc.
The extracts were combined and washed twice with water and once with saline. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in methanol (MeOH
) and 8d of triethylamine. The solution was stirred at RT for 2 hours and water was added. The methanol was removed under vacuum and the aqueous residue was purified with 2N HCl aqueous solution.
Acidified to H1.5. The aqueous mixture was extracted four times with EtOAc and the combined extracts were washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound.

Step B: 4-(t-Butyldimethylsilyloxy)benzyl alcohol The acid (Log) obtained in Step A was dissolved in 80 ml of THF, and this ? The liquid was cooled to OoC. 1 in THF solution
M lithium aluminum hydride (LAH) (53d) was added dropwise and the mixture was stirred at RT for 2 hours. Drop a saturated aqueous solution of sodium sulfate (411 dl) and add a small amount of THF.
was added to facilitate stirring. The mixture was stirred at RT overnight and then filtered through a pad of Celite. The precipitate cake was redissolved, stirred in hot THF, and the mixture was filtered. The hot THF treatment was repeated twice and all filtrates, including the first, were combined and concentrated under vacuum. The residue was distilled under reduced pressure to give the title compound (bp: 138° (2
)) Step C: 4-(t-butyldimethylsilyloxy)benzyl chloride Carbon tetrachloride 140d Alcohol obtained in Step B 6, 68
1 g of a solution of 9.12 g of triphenylphosphine
Reflux for 24 hours at 10"C. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in hexane and the mixture was filtered. The precipitate was allowed to evaporate until no product remained in the solid. Washed with hexane.Then the filtrate was vacuumed:a
The residue was distilled under reduced pressure to give a cloudy liquid.

The liquid was dissolved in silica gel (100:1 hexane:EtO
Flash chromatography with Ac) gave a clear liquid which was azeotroped three times with toluene. The title compound was then obtained by filtration through Millipore Acrodisc.

Step D: The title compound was obtained as a crystalline solid using the method of Step A, except that p-(t-butyldimethylsilyloxy)hydrocinnamic 4-hydroxybenzoic acid was replaced with p-hydroxyhydrocinnamic acid. mp84.5~85.5°
C Step E1.2-BisCp-(t~butyldimethylsilyloxy)benzyl)-acetic acid anhydride THF 3. O-diisopropyl amine 0.
The solution of 673 relative was cooled to O''C and the solution was dissolved in 1.72 rrdl of 2.4M n-butyllithium in hexane solution.
Processed with. The solution was stirred at 0°C for 45 min and then treated with 2.5 d of anhydrous THF and 448.
HMPAo, 317d was added to the 5-inch solution coat. The solution was stirred at RT for 1 hour, then the solution was cooled to -20 DEG C. and 410 .mu. of p-(t-butyldimethylsiloxy)benzyl chloride were added. The solution was stirred at RT for 1.5 hours and then cooled to 0°C. 2NH(/!p aqueous solution
H2 was added until obtained, and the mixture was diluted with EtOAc for 4 hours.
Extracted twice. The combined organic phases were washed three times with water and once with brine. The organic solution was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. Remove the residue with silica gel (
gradient 2.5:1 to 1:2 hexane:EtOAc)
Chromatography gave the title compound as a glassy paste.

Example 2, Step 5, except that the acid obtained in Step E was replaced with the acid obtained in Step E. The title compound was obtained using the method of E.

Step G: N-(2,2-bis(4-hydroxybenzyl)acetyl)-L-valyl-L-halyl-L-asparagyl-L-aspartyl-L-leucine Example 3, Step B ester is converted to Step F The title compound was obtained using the method of Example 3, Steps C and D, except that the ester obtained in .

p, m, r, (CD: 100) δ: 0.63 (d,
3B), 0.75(d, 38), 0.9-1.0
5 (m, 12H), 1.65 (m, 2H), 1.
80 (m, 3H), 2.70 (singing 48), 2.88
(m, 5B), 3.99(d, 11(), 4.0
5 (d, LH), 4.48 (broad, IH),
4.70 (m, LH) 4.80 (a+, LH),
6.70 (m, 4H), 7.04 ppm (m,
4H); A, S, (FAB): Dan/E 813
(M+H)"" Yoshikimaji N-(2,2-dibenzylacetyl)-L-valyl-L
-Baryl-L-asparagyl-L-asba methylene chloride 0.11111! A solution of 41 ml of dibenzyl acetic acid in 0.4 d of methylene chloride was added to a solution of dibenzyl acetic acid in 0.4 d of methylene chloride at 0°C and the mixture was stirred for 10 minutes at 0°C. The slurry was then filtered and the solids were chlorinated. Washed twice with methylene. The combined filtrates were concentrated under vacuum to give the title compound as a colorless glass.

Step B; N-(2,2-dibenzylacetyl)L-valyl-L-valyl-L-asparagyl-L-(0-t-butyl)aspartyl-L-(γ-methylleucyl) PepSnKA resin DMF2d middle step A solution of 96 mg of the anhydride obtained in step A and 6.1 mg of 4(dimethylamino)viridi7 (DMAP) was mixed with dry L-valyl L-valyl L-asparagyl-L-(
(0-t-butyl) aspartyl-L-Cr-methylleucyl) PepSyn K A resin (ξ Regen 9050
(synthesized using an automated peptide synthesis machine), and the mixture was left at RT for 24 hours, stirring occasionally in a sealed flask. The mixture was then filtered and the solids washed four times with anhydrous DMF, three times with methylene chloride, and three times with ether.

The solid was dried under vacuum to give the title compound as a colorless powder.

Presentation: N (2,2-dibenzylacetyl)-L-
Valyl L-Valyl L-Asparagyl-L-Aspartyl-L-Cr-Methylleucine The resin-bound peptide of Step B was suspended in 95:4:1 trifluoroacetic acid: ethanedithiol: thioanisole 4Id, and this mixture was gently stirred for 2 hours. The mixture was then filtered and the solids were stirred with the same solution 4- for 5 minutes. The mixture was filtered again and the solids were removed at 80%
Extracted with 4% aqueous acid. The combined extracts were concentrated under vacuum and the residue was extracted four times with ether. HPLC purification of the insoluble material provided the title compound.

pom, r, (DzO)δ: 0.35(d, 3H
), 0.59(d, 3)1), 0.91(d, 3
11) , 0.95 (d, 3H) , 0.92 (s,
911), 1.57 (m, IH), 1.99 (m
, LH), 2.51-3.09(m, 9H), 3
．． 70 (d, 18), 3.89 (d, IH),
4.18 (dd, IH), 4.62 (dd, LH)
, 4.72 (dd, IH), 7.20-7.36 p.
pm (m, Loll); M, S, (FAB):
m/e 795 (M+H)''Example 9 N-(2,2-dibenzylacetyl)-L-valyl-L
-Valyl-L-(N'-benzylasparagyl)-L-
A solution of 5.0 g of aspartic acid β-methyl ester hydrochloride and 8.98 ml of benzylamine in 40 d of aspartyl-L-(γ-methyl-MeOH) was stirred at 64°C for 4.5 hours. After 30 minutes a colorless crystalline solid appeared. The mixture started to grow. The mixture was then cooled to RT and filtered. The solid was washed five times with MeOII and twice with ether. The solid was then dried under vacuum to give the title compound as a colorless Obtained as crystalline powder, Ugly, p, 257-260°C0 Step B
:N'-(9-fluorenylmethoxycarbonyl)-
N'-Benzyl asparagine methylene chloride 40 - A mixture of 3.64 g of benzyl asparagine obtained in middle step A and 4.15 g of trimethylsilyl chloride was stirred under gentle reflux for 1 hour. The mixture was then cooled to O''C and 8.57 d of diisopropylethylamine was added slowly.

9-fluorenylmethyl chloroformate (4,04g
) was added and the mixture was stirred for 20 min at O''C and 1 h at RT. The clear solution was then concentrated under vacuum to give a viscous gum and 2.5% sodium bicarbonate. 1101
d and ether 100d. The phases were separated and the thick aqueous phase was washed three times with ether. Then carefully add 2N aqueous 11c! to the aqueous phase. ! , gradually adding p(1
It was made acidic to 2. The mixture was then filtered and the solid was dried under vacuum to give the title compound as a colorless powder.
p, 176-178 °C0 Wang Shudan: N'-(9-Fluorenylmethoxycarbonyl)-N'-benzylasparagine pentafluorophenyl ester EtOAc A solution of 822 mg of DCC in S ml was dissolved in EtOAc.
OAc 5 Substituted asparagine in step B of formation 1.99 g
and pentafluorophenol 787■ O″
Added in C. The mixture was stirred for 1 hour at O''C and 1 hour at RT.The mixture was then stirred in methylene chloride 40
d and the mixture was then filtered.

The solids were washed with methylene chloride and twice with ether. The solid was then dried under vacuum and then extracted twice with THF and twice with ether. The remaining solids were dried and then extracted twice with THF and twice with ether. The combined extracts were concentrated under vacuum to give the title compound and dicyclohexylurea in a 5.3:1 ratio. This mixture was used without purification.

Urchin tan: L-baryl-shi-valyl L-(N'benzylasparagyl)-L-aspartyl-L-(γ-methylleucyl) PeSynKA resin commercially available resin, N-9-fluorenylmethoxycarbonylpentafluorophenyl The title compound was prepared using a ξ Regen 9050 automatic peptide synthesis machine using the corresponding peptide units commercially available as esters and the ester obtained in step C.

Kumohodan: N-(2,2-dibenzylacetyl)L-
Valyl-L-valyl-L-(N'benzylasparagyl)-L-aspartyl-L-(γ
-Methylleucine) The title compound was obtained using the method of Example 8, Step C, except that the resin-bound protein of Example 8, Step B was replaced with the resin-bound peptide of Step B.

p, n+, r, (DzO)δ: 0.33 (d, 3
11) , 0.55 (d, 38), 0.88 (d,
3H), 0.90(s, 9H), 0.91(d,
3H), 1.56.1.69(dq, 2H), 1.
55 (m, 1ll), 11-96 (+18)2.
50-3.08 (m, 9H), 3.7Hd, IH)
, 3.90 (d, LH), 4.16 (dd, 18
), 4.34(s, 2H), 4.62(dd, I
H), 4.74 (dd, 11(), 7.20-7.4
2 ppm (m+ 158); M, S, (FAB)
: m/e 885 (M+H)" Example 10 L-tyrosyl-L-valyl-L-valyl-L-(O-methylaspartyl)-L-aspartyl-L-(T-methylleucine) Example 9, The title compound was obtained using the method of Example 9, Steps B-E, except that the substituted asparagine in Step A was replaced with aspartic acid β-methyl ester.

pom, r, (DzO)δ: 0.87-0.95(
m, 12H), 0.92(s.

98), 1.65.1.77 (dq, 2H), 2.
00(m, 2H), 2.72-2.98(m, 4
H), 3.70 (s, 311), 4.01 (d,
IH), 4.15 (d, LH), 4.28 (m,
2B), 6.85.7.10 ppm (q.

4H); Gate, S, (FAB): Engineering/Earth 751 (M+
H) "大迦艷LL上N-(9-fluorenylmethoxycarbonyl)-D-α
-Methylphenylalanyl-L-valyl-L-valyl-
L-asparagyl-L-aspartyl-L-leucine and N-(9-fluorenylmethoxycarbonyl)-L-α
-Methylphenylalanyl-L-valyl-L-valyl-
L-Asparagyl-L-aspartyl-L-leucine Step A: D, L-N-(9-fluorenylmethoxycarbonyl)-α-methylphenylalanine pentafluorophenyl ester Example 9, substituting asparagine into α The title compound was obtained using the method of Example 9, Steps B and C, except that -methylphenylalanine was substituted.

Second base: N (9-fluorenylmethoxycarbonyl)-D-α-methylphenylalanyl-L-valyl-L
-Baryl-L-asparagyl-L-aspartyl-L-
Leucine and N-(9-fluorenylmethoxycarbonyl)-L-α
-Methylphenylalanyl-L-valyl-L-valyl-
L-Asparagyl-L-aspartyl-L-leucine Example 3 Two diastereoisomers of the title compound were prepared using the method of Example 3, Steps C and D, except that the ester of Step B was replaced with the ester of Step A. A crude mixture of mer was obtained. A portion of this mixture was separated into individual pure diastereomers by HPLC purification and another portion was used as a mixture in the synthesis of Example I2.

Isomer A: pom, r, (DzO)δ: 1.02(m, 1B
+1), 1.25 (b, 311), 1.70 (m,
311), 2.15 (m, IH), 2.80 (m
, 4H), 3.15(m+2)1), 4.18(
d, If), 4.20(d, 1)1), 4.2
8(t, LH), 4.42(b, 211), 4
．． 71-4.79 (m, 3H), 7.0-8.0 p
pm (m, 13H); M, S, (FAB):
m/e 942 (M+H)” Isomer B: p, m, r, (DzO)δ: 1.02 (m, 18
H), 1.28 (b, 3H), 1.70 (m, 3)
ri, 2.18 (m, IH), 2.80 (m, 4
H), 3.10 (m, 28), 4.17 (d, L
H), 4.20 (d, 1ll), 4.28 (t,
IH), 4.42(b, 211), 4.80-4
．． 90 (m, 3) 1), 6.9-8.1 ppm (m
, 13H); M, S, (FAB): m/e
942 (M+H)” Example 12 D-α-methylphenylalanyl-shi-valyl L-valyl L-asparagyl-L-aspartyl-L-leucine and L-α-methylphenylalanyl-L-valyl-L -Baryl-I, -asparagyl-L-aspartyl-L-leucine A mixture of isomers of the substituted peptide of Example 11 (70 mg
) was dissolved in dimethylformamide (DMF) 1, and 0.111 ml of diethylamine was added to this solution. The solution was stirred at RT for 2 hours and then concentrated under vacuum. The residue was triturated with ether and then hexane. HPLC purification of the residue gave two isomers of the title compound.

Isomer A: p, m, r, (DzO)δ: 0.83 (d, 3H
), 0.89 (d, 38), 1.00 (m, 12
11), 1.49 (s, 3H), 2.09 (m,
2H), 2.80 (m, 5B), 3.22 (d,
18), 4.00 (d, IH), 4.25 (m,
2H), 4.72(m, IH), 4.85(m,
1)1), 7.35 ppm (m, 5H); M, S, (FAB): m/e 767 (M
+H)” Isomer B: p, m, r, (DzO)δ: 0.98 (m, 12
fl), 1.04 (d, 3H), 1.06 (d, 3
H), 1.48 (s, 38), 2.09 (m,
28), 2.76 (m, 5H), 3.25 (d,
1! (), 4.14 (d, 1ll), 4.23 (m
, IH) , 4.69 (m, LH) , 4.82 (
m, IH), 7.32 ppm (m, 58): M, S, (FAB): m/e 7
67 (M+H) "Ura theft squad, L-(α-methyltyrosyl)-L-valyl L-valyl L-asparagyl-L-aspartyl A: D,
L-N-(9-fluorenylmethoxycarbonyl)-α
-Methyltyrosine pentafluorophenyl ester The title compound was obtained using the method of Example 9, Step B, except that the substituted asparagine in Example 9, Step A was replaced with α-methyltyrosine.

Step B: D, L-(N-(9-fluorenylmethoxycarbonyl)-α-methyltyrosyl]-L-valyl-
L-valyl-L-asparagyl-L-aspartyl-L
-Leucine Using the method of Example 3, Steps C and D, except replacing the ester of Example 3, Step B with the ester to Step B, the title compound was obtained.

Step C: D, L-(α-methyltyrosyl)-Lvalyl-
L-valyl-L-asparagyl-L-aspartyl-L
-Leucine Two isomers of the title compound were obtained using the method of Example 12, except that the peptide of Example 11 was replaced with the peptide of Step B, and diethylamine was replaced with biheridine, and separated by HPLC purification.

Isomer A: p, m, r, (DzO)δ: 0.98 (m, 18
tl), 1.72 (m, 3H), 1.85 (s, 3
H), 1.93 (m, IH), 2.92 (m,
4H), 3.17(d, LH), 3.30(d,
18), 4.44 (m, 2H), 4.58 (m,
11), 4.95 (m, 2H), 6.80-7.
02 (q, 4H), 7.82 (d, IH), 8.
20(d, 1)1), 8.34(d, III),
8.39 (d, IH), 8.40 ppm (d,
LH); M, S, (FAB): m/e 73
6 (M+H)” isomer B: p, m, r, (DzO)δ: 0.9B(m, 18
fl), 1.71 (m, 311), 1.74 (s,
3tl), 1.88(m, 1ll), 2.92(
m, 4H), 3.28(d, IH), 3.34(
d, l[l), 4.28-4.38(m, 211
), 4.57 (m, 18), 4.95 (m, 18)
), 6.86-7.12 (q, 411), 7.82
(d, III), 8.10 (d, IH), 8.
13(d, IH), 8.19(d, IH), 8.
30 ppn+(d, LH); M, S, (FAB)
: m/e 736 (M+H)” Example 14 L-(N-(4-biphenylmethyl)tyrosyl]L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine IN Sodium hydroxide (NaOH) Aqueous solution (0,055
m1) in 0.165 d of water L-tyrosyl-L-valyl L-valyl L-asparagyl-L-aspartyl-
L-leucine (Millian 9050 automatic pef.

Using a Chido platform machine, it was added to a slurry of 20.0 cm in diameter. Dilute the cloudy solution with 0.22 d of acetonitrile,
Then, a solution of 20.2 μm of biphenyl-4-carboxaldehyde in 0.2 μl of acetonitrile was added. The mixture was stirred for 1 h at RT, then 0.2 h of acetonitrile was added.
d and sodium polyhydride in 0.05 d of water 4.2
A solution with a concentration of 1.0 mg was prepared. Add this liquid to 1.5 ml at RT.
Stir for an hour and then add 0.2 ml of acetic acid. The colorless dilute suspension was concentrated under vacuum and the residue was washed four times with ethyl ether. HPLC purification of the residue gave the title compound as a colorless powder.

p, m, r, (DzO)δ: 0.81-1.01(
m, 18H), 1.60(n+.

2H), 1.88(m, LH), 2.04(m,
l1l), 2.60-3.22 (3xdq, 6H
), 4.00 (d, IH), 4.09 (d, IH)
), 4.19 (m, 2H), 6.83.7.
08(q, 4H), 7.48-7.80 pp
m(m+90); M, S, (FAB): m/e 8BB
(M+H)”.

The following compound was prepared in a similar manner except that biphenyl-4-carboxaldehyde was replaced with the corresponding aldehyde and the peptide used in Example 14 was replaced with the corresponding peptide.

L-(N-benzyltyrosyl)-L-valyl-L-valyl-L-asparagyl-shi-aspartyl-L-leucine, L-(N-(3-phenoxybenzyl)tyrosyl]-L
-valyl L-valyl-L-asparagyl-L-aspartyl-L-leucine, L-(N-benzyltyrosyl)-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-(γ −
methylleucine), L-(N-(3-thienylmethyl)tyrosyl]-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine, L-[N-(carboxymethyl)tyrosyl]- L-valyl L-valyl-L-asparagyl-L-aspartyl-cy-leucine and L-(N-(4-carboxybenzyl)tyrosyl]L-
Valyl L-valyl-L-asparagyl-L-aspartyl-L-leucine Jisake L15 L-tyrosyl-valyl-L-valyl-L-asparagyl-cy-aspartyl-L-(N-methylleucine step A: N-(9-fluorenylmethoxycarbonyl)
-N-Methyl-L-leucine Example 9, Step A substituted asparagine was replaced with N-methyl-L-leucine
The title compound was obtained using the method of Example 9, Step B, except that -leucine was substituted.

Step B: N-(9-fluorenylmethoxycarbonyl)
-N-Methyl-L-leucyl anhydride The title compound was obtained using the method of Example 8, except that the substituted leucine in Step A was substituted for dibenzyl acetate.

Step C: N-(9-fluorenylmethoxycarbonyl)
-N-Methyl-L-Leucyl eSnKA DMF2 - A solution of 14.3 mg of leucyl anhydride from middle step B was added to 0.5 g of PepSyn KA resin. DM
4-N,N-dimethylaminopyridine 6 in Fo, 5d
．． 1 part of the solution was added and the mixture was gently shaken.

This mixture was left for 24 hours with occasional stirring. The mixture was then filtered and the solids were washed four times with DMF, three times with methylene chloride, and three times with ether. Drying under vacuum gave the title compound as a colorless powder.

Step D: L-tyrosyl-L-valyl-L-valyl-L-
Asparadyl-L-aspartyl-L-N-methylleucine) The title compound was obtained using the method of Example 1, except that the commercially available T-methylleucine unit was replaced with the peptide unit of Step C.

p, m, r, (DzO)δ: 0.81-0.99(
m, 15H), 1.38 (m18), 1.62-
1.83 (m, 2H), 1.98 (m, 2H),
2.50-2.93 (m, 4H), 3.04 (s,
3H), 3.12(d, 2H), 4.04(d,
IH), 4.15(d, LH), 4.27(t
, IH), 4.94 (dd,, IH), 5.27 (
dd, IH), 6.85-7.10 ppm (q,
4H); M, S, (FAR): m/e 736 (M
10H) "Taai history 7L ~ (N-(dibenzylcarbamyl)valyl) L-valyl L-asparagyl-L-aspartypyridine (1,
75g) and benzene 8 are added to a mixture of 4.4g of dibenzylamine and 12m2 of toluene, and the mixture is heated to O''C.
It was cooled to 20% phosgene solution in toluene (15d)
was added over a period of 45 minutes. This pasty mixture was diluted with 10 parts of toluene and stirred for 18 hours at RT. The mixture was filtered and the filtrate was concentrated under vacuum.

The residue was purified with silica gel (2:1 hexane:EtOAc).
Chromatography to give the title compound.

Step B: L-(N-(dibenzylcarbamyl)valyl)-L-valyl-L-asparagyl-L-aspartyl-shi-isyl-PepSyn KA Resin Example 8, Step B ester in Step A The title compound was obtained using the method of Example 8, Steps C and D, except that the corresponding Merrifield resin-bound peptide used in Example 8 was replaced with PepSyn KA resin-bound peptide in the resulting chloroformamide.

Step c: L-(N-dibenzylcarbatanyl)valyl]-L-valyl L-asparagyl L-aspartyl-L-leucine Example 8, replacing the resin-bound peptide of Step C with the resin-bound peptide of Step B Otherwise, the method of Example 8, Step C was used to obtain the title compound.

p, m, r, (CD30D) δ: 0.77 (d,
38), 0.88(d, 311), 0.95(d,
3H), 1.0 (m, 9H), 1.65 (m,
l1l) , 1.80(i, 2H) , 2.04(m
, IH) , 2.14(m, IH) , 2.70(
dd, IH), 2.80-2.94 (m, 3H),
4.17 (t, 2) 1), 4.40-4.55 (m,
3H), 4.66-4.76 (m, 3H), 4.8
0(t.

LH), 7.30(n+, 6H), 7.36(m
, 4H), 7.98-8.10ppm (m,
IB): M, S, (FAB): Dan/±782 (M10H)
"Example 17 L-(N-(diphenylcarbamyl)valyl]-L-paryl-L-asparagyl-L-aspartyl-L-leucine Example 3, step B ester to diphenylcarbamyl chloride, dioxane to DMF Example 3 except that
, Step C to obtain the title compound.

p, m, r, (CD3CO2D)δ: 0.84-
1.05 (m, 18H), 1.66-1.82 (m,
3H), 1.96-2.14 (m, 2B), 2.
82-3.06 (m.

4B), 4.27(d, LH), 4.44(d,
IH), 4.63 (n+, LH) 4.98 (m,
2H), 7.30 (m, 68), 7.40 p
pm (m, 411): Gate, S, (FAB): Engineering/
± 754 (M+1()” Example 18 L-(N-benzyltyrosyl)-L-valyl-L-valyl-L-(N', N'-dimethylasparagyl)-
L-Aspartyl-L-(r-methylleucine step A: N-(fluorenylmethoxycarbonyl)-N
-Benzyl-L-(4-t-butoxyphenylalanine) Asparagine in Example 2, Step C
The title compound was obtained using the same procedure as in Example 2, except that the compound was replaced with (t-butoxyphenylalanine).

Step A The title compound was obtained using the method of Example 8, Steps AC, except that the resin-bound pentapeptide of Example 8, Step B was replaced with the corresponding resin-bound pentapeptide.

p, m, r, (DzO)δ: 0.87-0.99(
m, 12H), 0.93(s9H), 1.65.
1.73 (dq, 2H), 1.92 (m, IH)
, 2.03 (m, IH) , 2.55-3.30 (m
, 611), 2.91 (s, 3H), 3.20 (s
, 3H), 3.55 (dd, IH), 3.
63.3.79(q, 28) 3.98(d, 1
8), 4.07(d, LH), 4.19(
dd, 1ll), 4.65(dd, 1B), 6
．． 80.7.04 (q, 4H), 7.30-7
．． 46pPnl (m, 5H); M, S, (FAR): Dan/e 854 (M+H)
◆Art student L-(N-bis(1-naphthylmethyl)acetylbaryl)-L-valyl-L-asparagyl-L-asbarthyl-L-leucine Unri Δnidimethyl-2,2-bis(1-naphthylmethyl) Malonate 2, ON sodium hydroxide methanolic solution (62d) was added to a solution of 14.2d dimethylmalonate in 50d methanol. The mixture was stirred for 30 min at RT and then 25 g of 1-bromomethylnaphthalene in 50 d of methanol
A solution of was added. The mixture was heated at 50"C for 1 h, then filtered and concentrated under vacuum. The residue was dissolved in EtOA
c 200 rd, and this solution is INHCj! Washed four times with aqueous solution and then with saline. The organic phase was dried over magnesium sulfate, then filtered and concentrated under vacuum. The residue was dissolved in silica gel (5:1 hexane:EtOA
Chromatography according to c) gave the title compound together with dimethyl-2-(1-naphthylmethyl)malonate.

2. A solution of 2.74 g of bis(naphthylmethyl)malonate in 2-bis(naphthylmethyl)acetic acid and methanol 10-27 d of aqueous sodium hydroxide.
Processed with. This mixture was heated to reflux overnight (105°C
), then the mixture was cooled to RT and then diluted with 70ml of water. The aqueous solution was washed twice with EtOAc and then the aqueous phase was cooled to O''C.
Gradually acidified to H1. This mixture was then extracted five times with ether. The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give the title compound.

Unlitan: 2.2-bis(l-naphthylmethyl)toluene chloride 4-Middle A suspension of 230 ml of the acid from step B was treated with oxalyl chloride ld and the reaction mixture was stirred at RT for 45 min. The solution was then concentrated under vacuum to give the title compound.

Step D: L-(N-bis(1-naphthylmethyl)acetylbaryl)-L-valyl-6-asbaragiru L-
Aspartyl-L-leucine in methylene chloride-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine (Biosearch 9
A suspension of 0.108 m of trimethylsilyl chloride and 0.108 m of trimethylsilyl chloride was stirred for 3 hours at RT using a 500 automatic peptide combiner.

Add diisopropylethylamine (0,186d),
Then, 76.8 μ of the acid chloride obtained in Step C was added, and the reaction solution was stirred at RT for 3 hours. The reaction mixture was then concentrated under vacuum and the residue was dissolved in ether and aqueous sodium bicarbonate. The aqueous phase was washed with ether and then made acidic. The aqueous mixture was then extracted three times with EtOAc. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated. HPLC purification of the residue gave the title compound.

pom, r, (DzO)δ: 0.28(d, 3H
), 0.52(d, 3H), 0.90(+++,
12H), 2.53 (m, 1B), 2.62 (m,
2B), 2.75-2.84 (m, 4H), 4.0
5 (m, IH), 4.15 (m, IH), 4.5
0(a+, 1B), 4.85(m, 2H), 7
．． 32-7.72 ppm (m.

7H); M, S, (PAB): m/e 881 (M+H
)”Otsuban main stand L-(3,5-short tyrosyl)-L-valyl-L-
Valyl-L-asparagyl-L-aspartyl-L-leucine Step A: L-(3,5-short tyrosyl)-L-valyl-L-valyl-L-asparagyl-L-(0-t-butyl) Aspartyl-shi-leucyl Pe5nKA resin 4-methylmorpholine 15.8 μl in 0.75 μl DMF
, (N-fluorenylmethoxycarbonyl)-3,5-
A solution of 684 mg of short tyrosine, 46.2 mg of [penzotriazolyloxy]tris[dimethylaminocophosphonium hexafluorophosphate, and 16.0 μg of 1-hydroxybenzotriazole 1 hydrate] was stirred for 10 minutes, then L -Baryl-L-valyl-L-asparagyl-L-(0-t-7'thyl)aspartyl-L-leucyl PepSyn K A resin (synthesized using Milligen 9050 automatic peptide synthesis machine) 300μ was added. . This mixture was diluted with 0.9 ml of DMF and stirred at RT for 24 hours. The mixture was then treated with 2 vdl of 20% v/v piperidine/DM F solution and the mixture was stirred for 15 minutes. The liquid was decanted and the solid treated with 3 ml of piperidine/DMF solution and stirred for 15 minutes. The liquid was decanted again and the solid was washed four times with DMF and three times with methylene chloride to give the title compound.

Yunchengdan: L-(3,5-short tyrosyl)-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine Example 8, Step C resin-bound peptide was added to Step A. The title compound was obtained using the method of Example 8, Step C, except that the resin-bound peptide was substituted.

p, m, r, (CD30D) δ: 0.90-1.10
(m, 18H) , 1.65(m, 11() , 1
．． 80 (m, 2H), 2.15 (m, 2H),
2.75 (m, 2H), 2.88 (m, 3) 1)
, 3.20 (dd, IH), 4.14-4.32 (
m, 3B), 4.44 (m, 1tl), 4.7
4(t, IH), 4.81(t, IH), 7.7
6(s, 2B), 8.08-8.31 ppm(m
t 311); M, S, (FAR): Engineering/± 973 (M+H)+
.

The above resin-bound peptide was converted into L-valyl-L-valyl-L-
(N', N'-dimethylasparagyl)-L-(0-
L-(3,5-short tyrosyl)-L-valyl was prepared using the same method as in steps A and B above, except that t-butyl)aspartyl-L-(γ-methylleucyl)-PepSyn K -L-valyl-L-(N'
, N'-dimethylasparagyl)-L-aspartyl-L-Cr-methylleucine) was obtained.

p, m, r, (CDsOD) δ: 1,00(m,
27H), 1.80-1.99 (m.

2H), 2.05-2.22 (m, 2H), 2.7
9-2.96 (m, 4H), 3.05 (m, IH)
, 3.21 (dd, IN), 4.16 (dd, I
H), 4.23 (m, 18), 4.40 (d,
1B) , 4.46 (+a, 18) , 4
．． 80 (m, 2H), 7.75 (s, 2H)
, 8.20 ppm (t, 2H); M, S, (F
AB): m/e 1016 (M+H)'Example 21 L-[N'-benzyloxycarbonyllysyl]L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine Example 20 The title compound was obtained, except that the induced tyrosine used in Example 1 was replaced with N-(fluorenylmethoxycarbonyl)-N'-benzyloxycarbonyllysine.

p, m, r, (CD30D) δ: 1.00 (m,
18H), 1.40-2.20 (m.

11H), 2.75 (m, IH), 2.89 (n+
, 2H) , 3.05 (m, IH) 3.16 (n+
, 2H) , 4.02(m, IH) , 4.27(
m, 2H), 4.45 (m, IH), 4.74 (
m, 18), 4.82 (broad t.

1) 1) , 5.11 (s, 2tl) , 7.38 (
m, 5H), 7.70-8.35ppm (m, 4
B); M, S, (FAB): m/e 821 (M
)""Exhibits L-lysyl-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-leucine Example 2, Step B
The crude residue was obtained using the method of Example 2, Step C, except that dimethylasparagine was replaced with the hexapeptide of Example 21, and purified by HPLC to give the title compound.

p, m, r, (CD30D) δ: 1. OO(m, 1
88), 1.55 (m, 2tl), 1.75 (m, 5
H), 11-95(+2H), 2.15(m,
28), 2.75 (m, 2H), 2.86 (m,
4H), 3.02(t, 2)1), 4.03(t
, IH) ,4.18 <+w, In) ,4.
26 (m, 1) 1), 4.44 (m, 1■), 4
．． 71 (m, IN), 4.8Ht, 1)1)
, 8.18-8.34 ppm (n+, 2H); M,
S, (FAB): m/e 687 (M+H)" Large turtle spot 1 Main L-tyrosyl-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-(5-flu 1-norvaline (11 , 72g) in a large quartz reaction vessel, cooled the vessel to -80°C, and added 100ml of anhydrous hydrofluoric acid.
f was condensed internally. The container was irradiated with ultraviolet light and trifluoromethylhypofluoride was bubbled into the container for 5 hours. A total of 80 psig of hypofluoride was used. UV irradiation was continued for a further 45 minutes, and then the solution was
Stored overnight at 0°C. The reaction solution was then concentrated under a stream of nitrogen, and the residue was then dissolved in 2N HCffi aqueous solution. The aqueous solution was concentrated under vacuum. HP the residue
LC purification provided the hydrochloride salt of the title compound and 4-fluoronorvaline hydrochloride.

Dissolve 5-fluoronorvaline hydrochloride in 10 d of water,
The solution was filtered through a plug of Celite. This solution was then diluted with isopropyl alcohol (1PrOH) for 75 d.
Diluted to volume and added 2d of propylene oxide. The solution was stirred until the free amino acids started to precipitate, then
Leave it for a minute. This mixture was diluted with 50 rrdl of 1PrOH and stored in the refrigerator overnight. The mixture was then filtered and the crystals were washed with 1PrOH and ether. The crystals were then dried under vacuum to yield the title compound.

Step B: L-tyrosyl-L-valyl-L-valyl-
L-Asparagyl-L-aspartyl-L-(5-fluoronorvaline) The title compound was prepared using the method of Example 15, except that N-methyl-L-leucine was replaced with 5-fluoronorvaline in Step A. I got it.

p, m, r, (DzO)δ: 0.89-1-00(
4xd+ 1211), 1.70-1.90(m+
48), 2.00(m+2H), 2.71-2.
96 (dq, 4H) 3.11 (d, 2H), 4.
05(d, 18), 4.15(d, 111), 4
．． 28.4.46 (dt, 2H), 4.40 (dd,
LH), 4.71-4.80 (m, 28), 6.
83.7.10 ppm (q, 411); M, S,
(FAB): m/e 726 (M+H)” Example 24 L-tyrosyl-L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-norvaline L-tyrosyl obtained in Example 1 -L-valyl-L-valyl-L-asparagyl-L-aspartyl-L-(2-allylglycine) was dissolved in 10% aqueous acetic acid 2, and 10% Pd/C13
, 5 ■ were added.

The mixture was stirred at RT for 2 hours under a hydrogen atmosphere of 1 atm. The reaction mixture was then filtered to remove the solids.
0% aqueous AcOH180% aqueous AcOH and 50% aqueous A
Washed with cOH. The combined filtrates were lyophilized. HPLC purification of the residue gave the title compound.

p, m, r, (020)δ: 0.87-1.00(m
, 15H), 1.3Hm.

Claims (1)

[Claims] 1. Formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I [In the formula, A^1 and A^2 independently represent a) isoleucine, b) leucine, c) norleucine, d) valine. , e) cyclohexylglycine, f) phenylglycine, g) N-methylisoleucine, h) N-methylvaline, i) phenylalanine, j) N-methylleucine or any of their enantiomers. A^3 has ▲mathematical formulas, chemical formulas, tables, etc.▼ {R^4 is hydrogen or methyl. R^5 is -NR^6R^7 or -OR^8 (R^6 and R^7 are independently j) hydrogen, k) C_3 to C_7 cycloalkyl, l) C_5 to C_7 cycloalkenyl, m) phenyl , n)-NH_2, C_1-C_4 alkyl, -SR^8
, -CO_2H or OR^8-substituted phenyl (R
^8 is H or C_1 to C_4 alkyl. ), o)
polycyclic aromatic ring system, p) C_1-C_6 alkyl, q) C_1-C_4 alkyl mono-substituted with k)-n) above, or R^6 and R^7 combined to form C_3- form a C_6 diradical or -NR^6R^7 is morpholino)
is}. A^4 is aspartic acid, N-methylaspartic acid or any of their enantiomers. A^5 is a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R^4 is as defined above. R^9 and R^1^0 are independently r) hydrogen, s) C_1 to C_6 alkyl, t) monofluoroalkyl, u) C_2-C_6 alkenyl, v) C_4-C_7 cycloalkyl, or R^9
and R^1^0 combine to form a C_3 to C_6 diradical). R^a is when m is 0 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or when m is 1 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or phenyl {R^1 is hydrogen or C_1 to C_6 alkyl It is. R^2 is w) C_3 to C_7 cycloalkyl, x) C_
5-C_7 cycloalkenyl, y) phenyl, z)-NH_2, C_1-C_4 alkyl, -SR^8
, -CO_2H, phenyl substituted 1 to 3 times with halogen or -OR^8, R^8 is H or C_1-C_4 alkyl, aa) polycyclic aromatic ring system, bb) w) ~ aa), -CO_2H or -NHR^
Alkyl monosubstituted with 1^1, R^1^1 is H or -CO_2CH_2C_6H_5, or R^2, when m is 1, is hydrogen or C_1-C_6 alkyl. R^3 is cc) hydrogen, dd) phenyl, ee) -NH_2, C_1~C_4 alkyl, -SR^
8, -CO_2H, phenyl substituted with 1 to 3 halogens or -OR^8 (R^8 is H) or C_1 to C_4 alkyl. ), ff) polycyclic aromatic ring system, gg) heteroaromatic ring system, dd) to gg) on hh) or -CO_2H with 1 or 2
C_1 to C_4 alkyl independently substituted, ii) -NHR^1^2 (R^1^2 is hh above), hydrogen, -CH_2CO_2H, -C(O)CHR^1^3
NH_2 or C_1 to C_6 alkyl, R^1^
3 is H or -SR^8, C_1-C_4 alkyl monosubstituted with -CO_2H. ). }. m is 0 or 1. n is 1 when m is 0, and 2 when m is 1. However, A^1 and A^2 are both valine, R^4 is hydrogen, R^5 is -NR^6R^7, R^6 is hydrogen, and R^7 is hydrogen or benzyl. And A^4
is aspartic acid, A^5 is leucine, and m
is 0, R^2 is not C_1-C_4 alkyl monosubstituted with one of the substituents w)-aa). ] A peptide having the following and a pharmaceutically usable salt thereof. 2, A^1 and A^2 are independently a) isoleucine, b) leucine, c) norleucine, d) valine, e) cyclohexylglycine, f) phenylglycine, g) N-methylisoleucine, h) N- Methylvaline, i) Phenylalanine, j) N-methylleucine, or any of their enantiomers, and A^3 is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {R^4 is hydrogen, and R^ 5 is -NR^6R^7(R
^6 and R^7 are independently hydrogen, methyl, ethyl, benzyl, or R^6 and R^7 are combined to form C
_3~C_5 diradical is formed or -NR^6R
^7 is morpholino), A^4 is aspartic acid, N-methylaspartic acid, or any of their enantiomers, and A^5 is the formula ▲ formula, There are chemical formulas, tables, etc. ▼ It is a peptide with (R^1^0 is isopropyl or t-butyl), R^1 is hydrogen, and R^2 is phenyl, benzyl or -NH_2, C_1~
C_4 alkyl, -SR^8, -CO_2H or -OR
phenyl or benzyl substituted with ^8 (R^8 is hydrogen or C_1-C_4 alkyl), m is 0 and n is 1, provided that A^1 and A^2 are both valine , R^4 is hydrogen, R^5 is -NR^6R^7, R^6 is hydrogen, R^7 is hydrogen or benzyl, A^4
Formula I according to claim 1, when R^2 is not C_1-C_4 alkyl monosubstituted with one of the substituents w) to aa) when is aspartic acid and A^5 is leucine
peptides and pharmaceutically usable salts thereof. 3. Formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A^1 and A^2 independently represent a) isoleucine, b) leucine, c) norleucine, d) valine, e) cyclohexylglycine, f ) phenylglycine, g) N-methylisoleucine, h) N-methylvaline, i) phenylalanine, j) N-methylleucine or any of their enantiomers. A^3 has ▲mathematical formulas, chemical formulas, tables, etc.▼ {R^4 is hydrogen or methyl. R^5-NR^6R^7 or -OR^8 (R^ and R^7 are independently j) hydrogen, k) C_3 to C_7 cycloalkyl, l) C_5 to C_7 cycloalkenyl, m) phenyl, n )-NH_2, C_1-C_4 alkyl, -SR^8
, -CO_2H or OR^8-substituted phenyl (R
^8 is H or C_1 to C_4 alkyl. ), o)
polycyclic aromatic ring system, p) C_1-C_6 alkyl, q) C_1-C_4 alkyl mono-substituted with k)-n) above, or R^6 and R^7 combined to form C_3- form a C_6 diradical or -NR^6R^7 is morpholino)
is}. A^4 is aspartic acid, N-methylaspartic acid or any of their enantiomers. A^5 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^4 is as described above. R^9 and R^1^0 are independently r) hydrogen, s) C_1 to C_6 alkyl, t) monofluoroalkyl, u) C_2-C_6 alkenyl, v) C_4-C_7 cycloalkyl, or R^9
and R^1^0 combine to form a C_3 to C_6 diradical). R_a is when m is 0 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or when m is 1 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or phenyl {R^1 is hydrogen or C_1 to C_6 alkyl . R^2 is w) C_3 to C_7 cycloalkyl, x) C_
5-C_7 cycloalkenyl, y) phenyl, z)-NH_2, C_1-C_4 alkyl, -SR^8
, -CO_2H, phenyl substituted 1 to 3 times with halogen or -OR^8, (R^8 is H or C_1-C_4 alkyl), aa) polycyclic aromatic ring system, bb) w on )~aa), -CO_2H or -NHR^
Alkyl mono-substituted with 1^1 (R^1^1 is H or -CO_2CH_2C_6H_5),
or R^2, when m is 1, is hydrogen or C_1-C_6 alkyl. R^3 is cc) hydrogen, dd) phenyl, ee) -NH_2, C_1~C_4 alkyl, -SR^
8, -CO_2H, phenyl substituted with 1 to 3 halogens or -OR^8 (R^8 is H, phenyl or C_1-C_4 alkyl), ff) polycyclic aromatic ring system, gg) dd) to gg) on a heteroaromatic ring system, hh) or -CO_2H with 1 or 2
C_1 to C_4 alkyl independently substituted, ii) -NHR^1^2 (R^1^2 is hh above), hydrogen, -CH_2CO_2H, -C(O)CHR^1^3
NH_2 or C_1 to C_6 alkyl, R^1^
3 is H or C_1-C_4 alkyl monosubstituted with -SR^8 or -CO_2H. ). m is 0 or 1. n is 1 when m is 0, and 2 when m is 1. However, A^1 and A^2 are both valine, R^4 is hydrogen, R^5 is -NR^6R^7, R^6 is hydrogen, and R^7 is hydrogen or benzyl. And A^4
is aspartic acid, A^5 is leucine, and m
is 0, R^2 is not C_1-C_4 alkyl monosubstituted with one of the substitutions w) to aa). ] In the method for synthesizing a peptide represented by the formula II and a pharmaceutically usable salt thereof, the formula II A_1A_2A_3A_4A_5PepSynKA resin
II (where A_1, A_2, A_3, A_4 and A_5
is as described above. ) The resin-bound pentapeptide represented by Formula III or Formula IV ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼III ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ IV (In the formula, R^a, m and n are described above. It is as it is done.X
is halogen or pentafluorophenoxy) in the presence of an organic nitrogen base, followed by removal of the resin to obtain the product. 4. An antiviral pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 5. A method for treating a viral infection in a mammal, which comprises administering the effective amount according to claim 1 to a mammal in need of treatment. 6. A method for treating a viral infection in a mammal, which comprises administering an effective amount of the compound according to claim 1 in combination with another antiviral acyclonucleoside or related compound to a mammal in need of treatment.